The invention relates to a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I 
in which
A is an alkyl radical having from 1 to 4 carbon atoms, characterized in that an aryl bromide of the formula II 
in which A is as defined in formula I, is reacted with a secondary or tertiary organolithium compound and CO2.
Ortho-alkylated benzoic acid derivatives of the formula I are important intermediates in industrial organic synthesis, e.g. in the preparation of fine chemicals, dyes and crop-protection compositions. They are also important intermediates in the preparation of medicaments, in particular in the preparation of inhibitors of the cellular Na+/H+ antiporter, which are known from EP 0 699 666 A1 or EP 0 758 644. In particular, 4-chloro-2-methylbenzoic acid is an intermediate in the synthesis of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonyl)benzamide, known from EP 0 699 666 A1 or N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, known from EP 0 758 644.
From classical organic synthesis (see on this subject standard works on organic synthesis, such as Houben-Weyl, Methoden der organischen Chemie [Methods in Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, or Beyer, Walter, Lehrbuch der organischen Synthese [Handbook of Organic Synthesis], S. Hirzel Verlag, Stuttgart), the preparation of ortho-alkylated benzoic acid derivatives from aniline derivatives by diazotization, Sandmeyer reaction and subsequent nitrile hydrolysis, or by ortho-metalation and subsequent alkylation of benzoic acid derivatives, is known. For economic and ecological reasons, these multistage synthesis sequences are unpracticable for industrial application.
H. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f. describes the synthesis of benzoic acid derivatives by lithiation of the corresponding aryl bromides and subsequent carboxylation. The preparation of 2-methylbenzoic acid by reaction of o-bromotoluene with n-butyllithium and subsequent carboxylation with solid CO2 achieves a yield of 83.8%. The reaction of 4-chlorobromobenzene with n-butyllithium and CO2 gives 4-chlorobenzoic acid with a 90% yield.
Preparation of the ortho-alkylated compounds of the formula I, in particular of 4-chloro-2-methylbenzoic acid, is impossible using the synthesis described above. Under the reaction conditions described in H. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f., and using the customary lithiation reagents n-butyllithium, n-hexyllithium, phenyllithium or methyllithium, the desired reaction does not take place at all or only with a very low yield.
These findings are further supported by the synthesis of 4-chloro-2-methylbenzoic acid which is described in U.S. Pat. No. 3,910,947. Firstly, 2-methyl-4-chloroaniline is diazotized and the diazonium salt is scavenged with KI to synthesize the very reactive 2-iodo-4-chlorotoluene, which is immediately converted into 4-chloro-2-methylbenzoic acid by reaction with n-butyllithium and CO2. The choice of the very reactive aryl iodide over the less expensive and more readily available bromine derivative confirms that it was hitherto impossible to convert the aryl bromides into the desired benzoic acid derivatives of the formula I in a satisfactory yield.
The object of the invention was therefore to develop a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I which permits the use of aryl bromides.
Surprisingly, it has been found that the reaction of the aryl bromides of the formula II with a secondary or tertiary organolithium compound as metalation agent takes place with a yield which is improved compared with the prior art or is very good.
As a result, we have provided a way of preparing the ortho-alkylated benzoic acid derivatives of the formula I by a reaction, which is easy to handle even on an industrial scale, as a one-pot synthesis under mild conditions and using bromine derivatives of the formula II, which are less expensive than the aryl iodides.
The invention therefore provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I 
characterized in that an aryl bromide of the formula II 
is reacted with a secondary or tertiary organolithium compound and CO2.
The invention further provides a process for the preparation of ortho-alkylated benzoic acids of the formula I, characterized in that a secondary organolithium compound chosen from the group consisting of sec-butyllithium, isopropyllithium, sec-amyllithium, 4-heptyllithium, cyclopropyllithium or cyclohexyllithium or a tertiary organolithium compound chosen from the group consisting of tert-butyllithium, tert-amyllithium, triethylmethyllithium, 1-methylcyclopentyllithium or adamantyllithium is used.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the reaction is carried out at temperatures between xe2x88x92100xc2x0 and +50xc2x0 C., and the reaction product is precipitated by adding an acid.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the reaction is carried out in an inert solvent chosen from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixtures thereof.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the aryl bromide of the formula II is introduced into an inert solvent, the secondary or tertiary organolithium compound is added, this reaction mixture is added dropwise to a CO2-saturated solvent, and the mixture is again saturated with CO2.
The invention preferably provides a process for the preparation of 4-chloro-2-methylbenzoic acid, characterized in that 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound and CO2.
The invention particularly preferably provides a process for the preparation of 4-chloro-2-methylbenzoic acid, characterized in that
a) 2-bromo-5-chlorotoluene is reacted with sec-butyllithium and CO2,
b) the reaction is carried out at temperatures between xe2x88x92100xc2x0 and +50xc2x0 C., and 4-chloro-2-methylbenzoic acid is precipitated by adding an acid,
c) the reaction is carried out in an inert solvent chosen from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixtures thereof, and
d) the 2-bromo-5-chlorotoluene is introduced into an inert solvent, the sec-butyllithium is added, this reaction mixture is added dropwise to a CO2-saturated solvent, and the mixture is again saturated with CO2.
The invention further provides for the use of 4-chloro-2-methylbenzoic acid prepared from the process described above as intermediate in the synthesis of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide.
The invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide characterized in that
in stage a) 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give 4-chloro-2-methylbenzoic acid,
in stage b) 4-chloro-2-methylbenzoic acid is reacted with chlorosulfonic acid, sodium sulfite and methyl iodide to give 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with benzylamine to give 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
in stage d) 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid is esterified with an alcohol to give the corresponding ester of 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
in stage e) the ester from stage d) is reduced to give the corresponding 4-amino-5-methylsulfonyl-2-methylbenzoic ester,
in stage f) 4-amino-5-methylsulfonyl-2-methylbenzoic ester is reacted with dimethoxytetrahydrofuran to give 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic ester, and
in stage g) 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic ester is reacted with guanidine to give N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide .
In stage d) preference is given to using an aliphatic alcohol having from 1 to 6 carbon atoms, such as, for example, methanol, ethanol, propanol, butanol, pentanol or hexanol. Particular preference is given to using methanol.
The invention further provides for the use of 4-chloro-2-methylbenzoic acid, prepared from the process described above, as intermediate in the synthesis of N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.
The invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4,5-di-(methylsulfonyl)benzamide, characterized in that
in stage a) 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give 4-chloro-2-methylbenzoic acid,
in stage b) 4-chloro-2-methylbenzoic acid is reacted with chlorosulfonic acid, sodium sulfite and methyl iodide to give 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with sodium methylthiolate and then oxidized with an oxidizing agent to give 2-methyl-4,5-di(methylsulfonyl)benzoic acid,
in stage d) 2-methyl-4,5-di(methylsulfonyl)benzoic acid is reacted with thionyl chloride to give 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride, and
in stage e) 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride is reacted with guanidinium chloride to give N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.
Preferred oxidizing agents in stage c) are H2O2, O2 or sodium perborate. Very particular preference is given to using sodium perborate.
The abbreviations used have the following meanings:
In the above formulae, A is alkyl and has from 1 to 4, preferably 1, 2 or 3, carbon atoms. Alkyl is preferably methyl, also ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Particular preference is given to methyl.
In the above formulae, the Cl substituent is preferably in the 3-, 4-, 5- or 6-position, particularly preferably in the 4-position relative to the position of the carboxyl group of the formula I.
The aryl bromides of the formula II are commercially available or can be prepared by methods known per se, as described, for example, in Houben-Weyl, Methoden der Organ. Chemie [Methods in Organic Chemistry].
CO2 is used in solid or gaseous form.
The invention also provides a process, as described, characterized in that secondary organolithium compounds chosen from the group consisting of sec-butyllithium, isopropyllithium, sec-amyllithium, 4-heptyllithium, cyclopropyllithium or cyclohexyllithium or a tertiary organolithium compound chosen from the group consisting of tert-butyllithium, tert-amyllithium, triethylmethyllithium, 1-methylcyclopentyllithium or adamantyllithium are used.
Preference is given to using secondary organolithium compounds chosen from the group consisting of sec-butyllithium, isopropyllithium, sec-amyllithium, 4-heptyllithium, cyclopropyllithium or cyclohexyllithium; particular preference is given to using sec-butyllithium.
The secondary or tertiary organolithium compounds listed above are commercially available or can be prepared by methods known per se, as described, for example, in Houben-Weyl, Methoden der Organ. Chemie [Methods in Organic Chemistry].
The invention also provides a process, as described, characterized in that the reaction is carried out at temperatures between xe2x88x92100xc2x0 and +50xc2x0 C. Preference is given to the temperature range between xe2x88x9250xc2x0 and +40xc2x0, particular preference to the temperature range between xe2x88x9220xc2x0 and +5xc2x0 C., very particular preference to the temperature range between xe2x88x9215xc2x0 and 0xc2x0 C.
The invention also provides a process, as described, characterized in that the reaction product, following customary work-up of the reaction mixture, is precipitated using acid. Customary work-up means: NaOH (10%) is added to the reaction mixture, the phases are separated, the organic phase is washed with NaOH (10%), and the aqueous phases are extracted with the inert solvent and separated off. The acid is chosen from a group of acids which include organic acids, preferably formic acid, acetic acid or propionic acid, or inorganic acids, preferably sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, or phosphoric acids such as orthophosphoric acid. Particular preference is given to using hydrochloric acid.
The invention also provides a process, as described, characterized in that the reaction is carried out in an inert solvent chosen from the group consisting of diethyl ether, MTB ether, THF, dioxane, toluene, hexane, petroleum ether or mixtures thereof. Particular preference is given to methyl tert-butyl ether.
The invention also provides a process, as described, characterized in that the aryl bromide of the formula II is introduced into an inert solvent chosen from the group consisting of diethyl ether, MTB ether, THF, dioxane, toluene, hexane, petroleum ether or mixtures thereof, particularly preferably MTB ether, the secondary or tertiary organolithium compound is added, this reaction mixture is added dropwise to a preferred volume of CO2-saturated solvent and the mixture is again saturated with CO2.
According to the process of the invention, the yields of ortho-alkylated benzoic acid derivatives of the formula I are generally between 30% and 90% when secondary or tertiary organolithium compounds are used, between 50% and 90% when secondary organolithium compounds are used, in particular between 70% and 90% when sec-butyllithium is used. Laborious purification steps by, for example, repeated recrystallization can be omitted. All temperatures above and below are given in xc2x0 C. The contents were determined, for example, after drying the crystals at 55xc2x0.
The invention also provides for the use of 4-chloro-2-methylbenzoic acid, prepared by the process described above, as intermediate in the synthesis of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide , known from EP 0 699 666 A1. Other intermediates of this synthesis sequence of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide, starting from the intermediate 4-chloro-2-methylbenzoic acid, are 2-methyl-4-chloro-5-methylsulfonylbenzoic acid, methyl 2-methyl-4-chloro-5-methylsulfonylbenzoate and methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate.
Accordingly, the invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamine, characterized in that
in the first stage a) according to the invention 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give the first intermediate 4-chloro-2-methylbenzoic acid,
in stage b) a methylsulfonyl group is introduced by reacting 4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfite and methyl iodide to give the corresponding intermediate 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
in stage c) the chlorine substituent is converted into a benzylamino group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with benzylamine to give the corresponding intermediate 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
in stage d) the free acid from stage c) is esterified with an alcohol, in particular methanol, and the corresponding intermediate 4-benzylamino-5-methylsulfonyl-2-methylbenzoate is obtained,
in stage e) the benzyl protective group is cleaved off by reduction to give the corresponding intermediate 4-amino-5-methylsulfonyl-2-methylbenzoate,
in stage f) the pyrrole group is introduced by reacting 4-amino-5-methylsulfonyl-2-methylbenzoate with dimethoxytetrahydrofuran and, correspondingly, the intermediate 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate is obtained and finally, as described in EP 0 699 666 (p. 8, line 19 to p. 10, line 1),
in stage g) by reaction of methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate with guanidine to give the end-product N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide, the guanidino group is introduced.
The invention also provides for the use of 4-chloro-2-methylbenzoic acid, prepared by the process described above, as intermediate in the synthesis of N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, known from EP 0 758 644 A1. Other intermediates of this synthesis sequence of N-diaminomethylene-2-methyl-4,5-di methylsulfonyl)benzamide, starting from the intermediate 4-chloro-2-methylbenzoic acid, are 2-methyl-4-chloro-5-methylsulfonylbenzoic acid, 2-methyl-4,5-di(methylsulfonyl)benzoic acid and 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride.
Accordingly, the invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4,5-di-(methylsulfonyl)benzamine, characterized in that
in the first stage a) according to the invention 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give the first intermediate 4-chloro-2-methylbenzoic acid,
in stage b) a methylsulfonyl group is introduced by reacting 4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfite and methyl iodide to give the corresponding intermediate 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
in stage c) the chlorine substituent is converted into a second methylsulfonyl group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium methylthiolate and then oxidizing the thioether with an oxidizing agent, in particular sodium perborate, to give the corresponding intermediate 2-methyl-4,5-di(methylsulfonyl)benzoic acid,
in stage d) the free acid from stage c) is converted using thionyl chloride into the acid chloride 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride as intermediate, and
in stage e) finally, as described in EP 0 758 644 (p.9, lines 10-20), by reaction of 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride with guanidinium chloride to give the end-product N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, the guanidino group is introduced.